1. Field of the Invention
The present invention is directed to solid dosage formulations containing a combination of valsartan, amlodipine and a diuretic such as hydrochlorothiazide, as well as to methods of making such solid dosage forms and a method of treating a subject with such solid dosage forms.
2. Related Background Art
The development of fixed-combination solid dosage formulations of certain active ingredients is challenging. As used herein, “fixed-combination” refers to a combination of two or more drugs or active ingredients presented in a single dosage unit such as a tablet or a capsule; further as used herein, “free-combination” refers to a combination of two or more drugs or active ingredients dosed simultaneously but as two or more dosage units. When formulating fixed-combination solid dosage formulations, the objective is to provide a patient-convenient combination dosage form of active ingredients that is bioequivalent to the corresponding free-combination of the same active ingredients and/or delivers a superior pharmacodynakic effect than the individual components. Development of fixed-combination dosage formulations that are bioequivalent to the free-combination is challenging due to the multiplicity of challenges arising from pharmacokinetic and pharmaceutical properties of the drugs sought to be combined.
For example, valsartan has an absolute oral bioavailability of only about 25% with a wide range of 10-35%. Valsartan also has pH dependent solubility whereby it ranges from very slightly soluble in an acidic environment to soluble in a neutral environment of the gastrointestinal tract. Further, development of a patient-convenient oral dosage form of valsartan is challenging due to its low bulk density. Amlodipine besylate is slightly soluble in water and has an absolute bioavailability of 64-90%. Hydrochlorothiazide is slightly soluble in water and has an oral bioavailability 60-80%. As a result of these complex biopharmaceutical properties, development of a fixed-combination dosage form of valsartan, amlodipine and hydrochlorothiazide that is bioequivalent to a free-combination thereof is challenging.
Accordingly, a fixed-combination solid dosage formulation of valsartan, amlodipine and hydrochlorothiazide that is bioequivalent to the corresponding free-combination would be desirable.